Hmx2 and Hmx3 Homeobox Genes Direct Development of the Murine Inner Ear and Hypothalamus and Can Be Functionally Replaced by Drosophila Hmx

Abstract

The Hmx homeobox gene family appears to play a conserved role in CNS development in all animal species examined, and in higher vertebrates has an additional role in sensory organ development. Here, we show that murine Hmx2 and Hmx3 have both overlapping and distinct functions in the development of the inner ear's vestibular system, whereas their functions in the hypothalamic/pituitary axis of the CNS appear to be interchangeable. As in analogous knockin studies of Otx and En function, Drosophila Hmx can rescue conserved functions in the murine CNS. However, in contrast to Otx and En, Drosophila Hmx also rescues significant vertebrate-specific functions outside the CNS. Our work suggests that the evolution of the vertebrate inner ear may have involved (1) the redeployment of ancient Hmx activities to regulate the cell proliferation of structural components and (2) the acquisition of additional, vertebrate-specific Hmx activities to regulate the sensory epithelia.

Wnt-dependent regulation of inner ear morphogenesis is balanced by the opposing and supporting roles of Shh

“…Similarly, embryos lacking Dlx5 fail to generate semicircular canals (Acampora et al 1999;Depew et al 1999;Merlo et al 2002). The apparent discordance in the mechanisms regulating Dlx5 and Hmx3, coupled with the finding that the expression of each gene is maintained in embryos deficient in the other, supports the notion that two pathways are functioning at early stages of inner ear development to promote the vestibulum (Merlo et al 2002;Wang et al 2004). A third pathway operating at a slightly later stage was also shown to promote outgrowth of the semicircular canals (Chang et al 2004b).…”

“…Interestingly, the absence or mislocalized expression of Bmp4 is a feature common to Wnt1/Wnt3a, Dlx5, and Hmx2/Hmx3 mutants ( Fig. 5; Merlo et al 2002;Wang et al 2004). For this reason, the three pathways involved in vestibular development described above may be integrating at different levels of a Bmp signaling cascade.…”

“…Hmx3 and Hmx2 overlap in the dorsolateral region of the otic vesicle and together are required for the development of all vestibular structures (Wang et al 2004). Similarly, embryos lacking Dlx5 fail to generate semicircular canals (Acampora et al 1999;Depew et al 1999;Merlo et al 2002).…”

Head Bobber: An Insertional Mutation Causes Inner Ear Defects, Hyperactive Circling, and Deafness

“…Similar to head bobber mice, single-and doubledeletion mutations in the Hmx3 (Nkx5-1) and Hmx2 (Nkx5.2) genes result in mice that have hyperactivity, head tilting, and circling behaviors but do not have defects in the stria or collapse of Reissner's membrane (Hadrys et al 1998;Wang et al 2001Wang et al , 2004Wang et al , 1998. In the ear, the defects affect cell fate and vestibular morphogenesis, including development of the vestibular ganglion (Hadrys et al 1998;Wang et al 2001Wang et al , 2004Wang et al , 1998.…”

“…In the ear, the defects affect cell fate and vestibular morphogenesis, including development of the vestibular ganglion (Hadrys et al 1998;Wang et al 2001Wang et al , 2004Wang et al , 1998. Since the anterior canal is first to develop and the lateral last (Martin and Swanson 1993;Sher 1971), development of the remnant anterior canal in hb/hb suggests that semicircular canal development was initiated but was not maintained.…”